👤 Alissa Semaan

The molecular characterization of male breast cancer (MaBC) has received limited attention in research, mostly because of its low incidence rate, accounting for only 0.5% to 1% of all reported cases of breast cancer each year. Managing MaBC presents significant challenges, with most treatment protocols being adapted from those developed for female breast cancer. Utilizing whole-genome sequencing (WGS) and state-of-the-art analyses, the genomic features of 10 MaBC cases (n = 10) were delineated and correlated with clinical and histopathologic characteristics. Using fluorescence in situ hybridization, an additional cohort of 18 patients was interrogated to supplement WGS findings. The genomic landscape of MaBC uncovered significant genetic alterations that could influence diagnosis and treatment. We found common somatic mutations in key driver genes, such as FAT1, GATA3, SMARCA4, and ARID2. Our study also mapped out structural variants that impact cancer-associated genes, such as ARID1A, ESR1, GATA3, NTRK1, and NF1. Using a WGS-based classifier, homologous recombination deficiency (HRD) was identified in 2 cases, both presenting with deleterious variants in BRCA2. Noteworthy was the observation of FGFR1 amplification in 21% of cases. Altogether, we identified at least 1 potential therapeutic target in 8 of the 10 cases, including high tumor mutational burden, FGFR1 amplification, and HRD. Our study is the first WGS characterization of MaBC, which uncovered potentially relevant variants, including structural events in cancer genes, HRD signatures, and germline pathogenic mutations. Our results demonstrate unique genetic markers and potential treatment targets in MaBC, thereby underlining the necessity of tailoring treatment strategies for this understudied patient population. These WGS-based findings add to the growing knowledge of MaBC genomics and highlight the need to expand research on this type of cancer. Show less

Chemokine signaling regulates cell migration and tumor metastasis. CXCL12, a member of the chemokine family, and its receptor, CXCR4, a G protein coupled receptor (GPCR), are key mediators of prostate-cancer (PC) bone metastasis. In PC cells androgens activate CXCR4 gene expression and receptor signaling on lipid rafts, which induces protease expression and cancer cell invasion. To identify novel lipid-raft-associated CXCR4 regulators supporting invasion/metastasis, we performed a SILAC-based quantitative proteomic analysis of lipid-rafts derived from PC3 stable cell lines with overexpression or knockdown of CXCR4. This analysis identified the evolutionarily conserved phosphatidylinositol 4-kinase IIIα (PI4KIIIα), and SAC1 phosphatase that dephosphorylates phosphatidylinositol-4-phosphate as potential candidate CXCR4 regulators. CXCR4 interacted with PI4KIIIα membrane targeting machinery recruiting them to the plasma membrane for PI4P production. Consistent with this interaction, PI4KIIIα was found tightly linked to the CXCR4 induced PC cell invasion. Thus, ablation of PI4KIIIα in CXCR4-expressing PC3 cells reduced cellular invasion in response to a variety of chemokines. Immunofluorescence microscopy in CXCR4-expressing cells revealed localized production of PI4P on the invasive projections. Human tumor studies documented increased PI4KIIIα expression in metastatic tumors vs. the primary tumor counterparts, further supporting the PI4KIIIα role in tumor metastasis. Furthermore, we also identified an unexpected function of PI4KIIIα in GPCR signaling where CXCR4 regulates PI4KIIIα activity and mediate tumor metastasis. Altogether, our study identifies a novel cross-talk between PI4KIIIα and CXCR4 in promoting tumor metastasis and suggests that PI4KIIIα pharmacological targeting may have therapeutic benefit for advanced prostate cancer patients. Show less